Despite the high mortality and morbidity associated with ischemic strokes, which result in loss of blood flow to a part of the brain, current therapies are only partially effective and not effective at all unless given within a very short window following the stroke. After a stroke, brain cells die for lack of oxygen in a spreading penumbra downstream from the clot. Time is of the essence in starting therapy, but many strokes are silent, or go untreated for lack of facilities equipped to properly diagnose stroke and begin therapy. Recombinant tissue plasminogen activator (r-tPA) represents the current treatment paradigm for acute stroke. However, even if r-tPA is given promptly, within a generally recognized critical period of 3 hours following symptom onset, there is no improvement in overall outcomes according to some studies, and there is an increased risk of hemorrhagic conversion (to ICH, “intracranial hemorrhage”) and early mortality.
Similarly, administration of heparin or other anticoagulants is generally ineffective in relieving stroke and may be associated with an unacceptably high incidence of ICH. Conservative therapy is just aspirin, but the condition remains the number two cause of death and disability worldwide.
Adjunct therapies have been tested. Surprisingly, ultrasonic imaging machines, including those designed for transcranial Doppler, were found by Alexandrov to potentiate recanalization following administration of r-tPA, and the improvement was associated with a significant decrease in functional impairment at 3 months post-stroke following combined treatment with r-tPA and Doppler ultrasound during a critical period of about 3 hours immediately following onset. However, as reported in U.S. Pat. No. 6,733,450 to Alexandrov, complete recanalization was achieved in only 30% of patients and no improvement was noted in 30% of patients treated with r-tPA and ultrasound in combination. 7.5% of patients developed intracerebral hemorrhage. There is room for further improvement.
Using transcranial color-coded doppler (TCCD) continuous monitoring without the use of r-tPA, Cintas reported a higher rate of partial recanalization in a study (n=6) reported in 2002 (Stroke 33:626-28). A focused 2 MHz transducer was used and the transducer was held in place on a metal frame following diagnostic sonography. A focused beam intensity of 415 mW/cm2 was aimed at a 1 cm length of the MCA containing the occlusion, a treatment that requires a high level of skill and instrumentation to deliver.
Other innovations have been made by Lauer, Alexandrov, Holland, Culp, Unger, Voorhees, Vortman, Chopra, Baron, Furuhata, Horzewski, Hansmann, Smith, Browning, Daffertshoffer, and by others.
However, all studies to date have been problematic in one way or another. The device of the invention differs from the devices used in the earlier CLOTBUST studies (Alexandrov et al 2004a & 2004b) and in studies by Sharma et al (2008a & 2008b) and Cintas (2002) in that those studies used a single diagnostic transducer unit manually operated by a skilled sonographer to establish a preferred orientation, and the transducer unit was then typically locked into place using a cumbersome support frame. Alexandrov recently summarized the art in that, “One of major limitations of this technology that there are no reliable head frames for transducer fixation, and most studies are to be carried out hand-held” (Tsivgoulis 2007 J Clin Neurol 3:1-8). The head frames generally have a skeleton of surgical steel and are weighty and opaque to CT or MRI scanners.
Because the transducer units of the art must be carefully placed by sonographic imaging of the cerebral vasculature, generally with Doppler imaging, valuable time is lost. A solution to this problem as described here is to position a headset of the invention without diagnostic imaging as a guide, but instead using mechanical alignment guides by reference to external craniological landmarks and to use non-focused ultrasound transducers. Craniological landmarks are selected that define a reference plane tangential to the anterior and posterior cingulate processes, the reference plane with x, y and z coordinates, and thus the location of the cerebrovascular nexus where most strokes occur. The need for sonographer-controlled aiming is eliminated by preset angulation of each transducer relative to the external landmarks and the reference plane defined thereby.
Also consequent to the use of trained operators to set up devices for transcranial sonothrombolysis, there is in the art a general lack of consistency from operator to operator and from institution to institution. The reproducibility of transcranial ultrasound would be increased by provision for an apparatus that is configured to autonomously deliver a prescribed regimen of ultrasound with a fixed anatomical orientation. A solution to the problem of reproducibility, which avoids the need for a precise localization of a clot, is to provide transducers on a headset that is positioned as described above, so that the relationship of the transducer arrays to the cerebral vasculature is established by reference to external craniological landmarks, and to then insonate in a way that is generally safe; independent of the results of any diagnostic study.
In a preferred embodiment, the apparatus may be used where hemorrhage is present or is likely to occur, as is not infrequently the case in stroke and particular in stroke that has been treated with anticoagulants or thrombolytic drugs.
In another embodiment of the inventive apparatus, the autonomous insonation regime includes cyclical repetition of trains of pulses of ultrasound, where each cyclical repetition of pulse trains is a “metapulse” having a vectored and temporal distribution of individual pulse trains, with provision for alternating from transducer to transducer and limiting duty cycle so that no assisted cooling is required. The amplitude of ultrasound emitted by each transducer may be adjusted to compensate for differences due to transducer-to-transducer variability in manufacture, a distinct technological advance in the art.
Portability remains a problem. Several features of the apparatus of the invention operate in synergy to enable the device to be transported with the subject without interrupting insonation, so that the subject may be transported or even walk while wearing the apparatus. By providing a lightweight, portable power supply in a pocket-sized housing attached to the headset by a cable, the need for attachment to a stationary power supply is eliminated. Low power consumption for extended use is achieved by reducing the duty cycle of the insonation and by configuring emissions in the form of pulse trains having a pulse repetition frequency (PRF) and a metapulse cycle repetition frequency (MCRF), by using resonant circuit elements, lower driving voltage, and by operating so that assisted cooling is not required. Elimination of energy-consuming cooling means is made possible by alternating actuation of individual transducers so that heat may dissipate in spaces between transducers during pulse intervals by passive conductive and convective mechanisms, eliminating the need for assisted cooling, such as with fans or circulating coolant.
By making the headset from a lightweight and X-ray translucent material, and by configuring ultrasonic emissions from the headset transducer arrays for low power consumption, the apparatus becomes fully portable, may be transported with the patient, and operation of the apparatus need not be interrupted while the subject is, for example, inserted into a diagnostic machine for computerized tomography (CT). The option of beginning and continuing insonation while awaiting definitive diagnosis by angiographic CT is made possible by tethering the electronics and power supply away from the headset assembly at the end of a cable so that diagnostic imaging is not interfered with and by use of plastic structural members. Because transverse sections are commonly used in imaging to visualize the cerebral arterial nexii, in one embodiment the transducer array is mounted supracranially so that imaging may be performed without interference.
The option of portable extended delivery of transcranial ultrasound for sonothrombolysis has been a longstanding need but has not previously been realized. The apparatus of the invention is configured for continuous autonomous operation for 2 hrs, for 4 hours, for up to 12 hours, or for longer with intermittent operation, without operator intervention or recharge, and hence may be used non-invasively in stroke prophylaxis, as a follow-up to administration of thrombolytic drugs, and for other neurovascular conditions where persistent exposure to low amplitude ultrasound is desirable.
Tools for non-invasive sonothrombolysis, as known in the art, remain experimental, and have not yet resulted in changes to the basic standard of care for stroke or dramatically improved the prognosis. Recent clinical trials supplementing r-tPA with transcranial ultrasound resulted in an unacceptably high incidence of intracranial hemolysis (ICH) and the trials were stopped. Since then, no advance in the clinical use of transcranial sonothrombolysis has been reported.
Importantly, centralized stroke centers that specialize in stroke diagnosis and advanced treatment—absent sonothrombolysis—have improved mortality and morbidity following stroke by only 20% overall. Each year in the United States, 700,000 strokes occur and more than 150,000 deaths are caused by strokes. Following a stroke, life expectancy drops to 5 years or less for most victims. When r-tPA is given alone, reperfusion is not achieved in 74% of cases (according to del Zoppo et al, 1992, Ann Neurol 32:78-86). Thus there is a need for new solutions and improvements in therapy. The problems of existing invasive therapies, the risk of administration of r-tPA among them, continue to outweigh potential benefits in the estimation of many physicians, and there is a long-felt and unmet need for a therapy for stroke having improved efficacy; a need for a therapy that is non-invasive and safe; a need for a therapy that does not require trained sonographers to administer and instead relies on craniological landmarks to align a plurality of transducer arrays for insonation of the cerebral vasculature associated with most strokes; a need to begin treatment prior to a definitive diagnosis by CT or MRI; the need for reproducible therapy based on autonomous administration of a cyclical regime insonation at defined frequency, pulse repetition frequency (PRF), pulse train repetition frequency (PTRF), pulse duration, peak rarefaction pressure and beam centerline vector; and the need to begin treatment prior to administration of r-tPA, while not limited thereto.
Serendipitously, we have unexpectedly discovered that the device we have developed for stroke is also suitable more generally for non-invasive therapies in a variety of neurological and vascular conditions such as migraine, intracranial hypertension, hydrocephalus and even the common headache, which are also associated with significant loss of productivity and quality of life, and also may be used with negligible or minimal risk as an adjunct therapy in drug delivery and for release of mediators of physiological function such as endogenous tissue plasminogen activator, nitric oxide, and prostaglandins.